There is an increased cardiovascular risk in individuals with posttraumatic stress disorder (PTSD). However, the causal relationship between cardiovascular risk/hypertension and PTSD remains unclear, and the mechanisms underlying the high comorbidity of PTSD with cardiovascular diseases are not well understood. Evidence suggests that the actions of commonly used blood pressure medications that target the renin- angiotensin system extend beyond blood pressure reduction and may have therapeutic effects on trauma- related disorders, such as PTSD. The mechanisms for how angiotensin II (Ang II) signaling through Ang-II type 1 receptors (AT1R) affects trauma response and symptoms are not clear. Ang-II is released during severe stress, and there is some evidence for central AT1aRs to potentially affect PTSD through direct effects on fear circuit activation. An alternate mechanism however is that peripheral Ang II signaling may also contribute to development of PTSD through exposure of the central nervous system to inflammatory signaling via disruption of the blood brain barrier (BBB) during and after trauma. The BBB, by being the primary barrier separating the peripheral and central systems, is crucial in the regulation of central homeostasis. BBB integrity is disrupted by hypertension and severe stress, and is associated with one of the strongest trauma-related risk factors for PTSD, traumatic brain injury. AT1R activation of Gq signaling disrupts the tight junctions of endothelial cells, allowing larger molecules such as proteins to pass through. Here we propose that severe stress increases peripheral Ang II, which activates endothelial AT1Rs, leading to both increased blood pressure and BBB disruption. The trauma-induced BBB breakdown may then enable access of peripheral inflammatory signaling molecules to the brain, increasing the risk for PTSD. We propose to test this hypothesis by using cell-type specific genetic and chemogenic tools to probe the contribution of peripheral AT1aR signaling to enduring central inflammatory and behavioral responses to trauma. Aim 1 will test the hypothesis that peripheral AT1aR signaling is necessary for trauma-induced BBB disruption, and enduring central inflammation and PTSD-like behavior. Aim 2 will test the hypothesis that Gq/11 signaling in endothelial cells during and after trauma is sufficient to disrupt BBB integrity and induce enduring inflammatory and behavioral responses to trauma. Thus, the proposed studies will identify the relationship between peripheral and central renin-angiotensin system to lead to increased central immune signaling and enduring trauma symptoms, and provide insights into the contribution of BBB permeability to trauma risk and symptom maintenance.